Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: A role for mast cells

Lisheng Zhang, Jiao Hui Wu, James C. Otto, Susan Gurley, Elizabeth R. Hauser, Sudha K. Shenoy, Karim Nagi, Leigh Brian, Virginia Wertman, Natalie Mattocks, Jeffrey H. Lawson, Neil J. Freedman

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aims Chronic kidney disease (CKD) is a powerful independent risk factor for cardiovascular events, including vein graft failure. Because CKD impairs the clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote vein graft neointimal hyperplasia. Methods and results We modelled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduced glomerular filtration rate by 60%, and we modelled vein grafting with inferior-vena-cava-to-carotid interposition grafting. CKD increased vein graft neointimal hyperplasia four-fold, decreased vein graft re-endothelialization two-fold, and increased serum levels of interleukin-9 (IL-9) five-fold. By quantitative immunofluorescence and histochemical staining, vein grafts from CKD mice demonstrated a ~two-fold higher prevalence of mast cells, and a six-fold higher prevalence of activated mast cells. Concordantly, vein grafts from CKD mice showed higher levels of TNF and NFκB activation, as judged by phosphorylation of NFκB p65 on Ser536 and by expression of VCAM-1. Arteriovenous fistula veins from humans with CKD also showed up-regulation of mast cells and IL-9. Treating CKD mice with IL-9-neutralizing IgG reduced vein graft neointimal area four-fold, increased vein graft re-endothelialization ~two-fold, and reduced vein graft total and activated mast cell levels two- and four-fold, respectively. Treating CKD mice with the mast cell stabilizer cromolyn reduced neointimal hyperplasia and increased re-endothelialization in vein grafts. In vitro, IL-9 promoted endothelial cell apoptosis but had no effect on smooth muscle cell proliferation. Conclusion CKD aggravates vein graft disease through mechanisms involving IL-9 and mast cell activation.

Original languageEnglish (US)
Pages (from-to)1551-1559
Number of pages9
JournalCardiovascular Research
Volume113
Issue number13
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Fingerprint

Interleukin-9
Chronic Renal Insufficiency
Mast Cells
Veins
Transplants
Hyperplasia
Cromolyn Sodium
Vascular Cell Adhesion Molecule-1
Arteriovenous Fistula
Inferior Vena Cava

Keywords

  • Cytokines
  • Endothelial cells
  • Mast cells
  • Neointimal hyperplasia
  • Smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Zhang, L., Wu, J. H., Otto, J. C., Gurley, S., Hauser, E. R., Shenoy, S. K., ... Freedman, N. J. (2017). Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: A role for mast cells. Cardiovascular Research, 113(13), 1551-1559. https://doi.org/10.1093/cvr/cvx177

Interleukin-9 mediates chronic kidney disease-dependent vein graft disease : A role for mast cells. / Zhang, Lisheng; Wu, Jiao Hui; Otto, James C.; Gurley, Susan; Hauser, Elizabeth R.; Shenoy, Sudha K.; Nagi, Karim; Brian, Leigh; Wertman, Virginia; Mattocks, Natalie; Lawson, Jeffrey H.; Freedman, Neil J.

In: Cardiovascular Research, Vol. 113, No. 13, 01.11.2017, p. 1551-1559.

Research output: Contribution to journalArticle

Zhang, L, Wu, JH, Otto, JC, Gurley, S, Hauser, ER, Shenoy, SK, Nagi, K, Brian, L, Wertman, V, Mattocks, N, Lawson, JH & Freedman, NJ 2017, 'Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: A role for mast cells', Cardiovascular Research, vol. 113, no. 13, pp. 1551-1559. https://doi.org/10.1093/cvr/cvx177
Zhang, Lisheng ; Wu, Jiao Hui ; Otto, James C. ; Gurley, Susan ; Hauser, Elizabeth R. ; Shenoy, Sudha K. ; Nagi, Karim ; Brian, Leigh ; Wertman, Virginia ; Mattocks, Natalie ; Lawson, Jeffrey H. ; Freedman, Neil J. / Interleukin-9 mediates chronic kidney disease-dependent vein graft disease : A role for mast cells. In: Cardiovascular Research. 2017 ; Vol. 113, No. 13. pp. 1551-1559.
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abstract = "Aims Chronic kidney disease (CKD) is a powerful independent risk factor for cardiovascular events, including vein graft failure. Because CKD impairs the clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote vein graft neointimal hyperplasia. Methods and results We modelled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduced glomerular filtration rate by 60{\%}, and we modelled vein grafting with inferior-vena-cava-to-carotid interposition grafting. CKD increased vein graft neointimal hyperplasia four-fold, decreased vein graft re-endothelialization two-fold, and increased serum levels of interleukin-9 (IL-9) five-fold. By quantitative immunofluorescence and histochemical staining, vein grafts from CKD mice demonstrated a ~two-fold higher prevalence of mast cells, and a six-fold higher prevalence of activated mast cells. Concordantly, vein grafts from CKD mice showed higher levels of TNF and NFκB activation, as judged by phosphorylation of NFκB p65 on Ser536 and by expression of VCAM-1. Arteriovenous fistula veins from humans with CKD also showed up-regulation of mast cells and IL-9. Treating CKD mice with IL-9-neutralizing IgG reduced vein graft neointimal area four-fold, increased vein graft re-endothelialization ~two-fold, and reduced vein graft total and activated mast cell levels two- and four-fold, respectively. Treating CKD mice with the mast cell stabilizer cromolyn reduced neointimal hyperplasia and increased re-endothelialization in vein grafts. In vitro, IL-9 promoted endothelial cell apoptosis but had no effect on smooth muscle cell proliferation. Conclusion CKD aggravates vein graft disease through mechanisms involving IL-9 and mast cell activation.",
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T2 - A role for mast cells

AU - Zhang, Lisheng

AU - Wu, Jiao Hui

AU - Otto, James C.

AU - Gurley, Susan

AU - Hauser, Elizabeth R.

AU - Shenoy, Sudha K.

AU - Nagi, Karim

AU - Brian, Leigh

AU - Wertman, Virginia

AU - Mattocks, Natalie

AU - Lawson, Jeffrey H.

AU - Freedman, Neil J.

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N2 - Aims Chronic kidney disease (CKD) is a powerful independent risk factor for cardiovascular events, including vein graft failure. Because CKD impairs the clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote vein graft neointimal hyperplasia. Methods and results We modelled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduced glomerular filtration rate by 60%, and we modelled vein grafting with inferior-vena-cava-to-carotid interposition grafting. CKD increased vein graft neointimal hyperplasia four-fold, decreased vein graft re-endothelialization two-fold, and increased serum levels of interleukin-9 (IL-9) five-fold. By quantitative immunofluorescence and histochemical staining, vein grafts from CKD mice demonstrated a ~two-fold higher prevalence of mast cells, and a six-fold higher prevalence of activated mast cells. Concordantly, vein grafts from CKD mice showed higher levels of TNF and NFκB activation, as judged by phosphorylation of NFκB p65 on Ser536 and by expression of VCAM-1. Arteriovenous fistula veins from humans with CKD also showed up-regulation of mast cells and IL-9. Treating CKD mice with IL-9-neutralizing IgG reduced vein graft neointimal area four-fold, increased vein graft re-endothelialization ~two-fold, and reduced vein graft total and activated mast cell levels two- and four-fold, respectively. Treating CKD mice with the mast cell stabilizer cromolyn reduced neointimal hyperplasia and increased re-endothelialization in vein grafts. In vitro, IL-9 promoted endothelial cell apoptosis but had no effect on smooth muscle cell proliferation. Conclusion CKD aggravates vein graft disease through mechanisms involving IL-9 and mast cell activation.

AB - Aims Chronic kidney disease (CKD) is a powerful independent risk factor for cardiovascular events, including vein graft failure. Because CKD impairs the clearance of small proteins, we tested the hypothesis that CKD exacerbates vein graft disease by elevating serum levels of critical cytokines that promote vein graft neointimal hyperplasia. Methods and results We modelled CKD in C57BL/6 mice with 5/6ths nephrectomy, which reduced glomerular filtration rate by 60%, and we modelled vein grafting with inferior-vena-cava-to-carotid interposition grafting. CKD increased vein graft neointimal hyperplasia four-fold, decreased vein graft re-endothelialization two-fold, and increased serum levels of interleukin-9 (IL-9) five-fold. By quantitative immunofluorescence and histochemical staining, vein grafts from CKD mice demonstrated a ~two-fold higher prevalence of mast cells, and a six-fold higher prevalence of activated mast cells. Concordantly, vein grafts from CKD mice showed higher levels of TNF and NFκB activation, as judged by phosphorylation of NFκB p65 on Ser536 and by expression of VCAM-1. Arteriovenous fistula veins from humans with CKD also showed up-regulation of mast cells and IL-9. Treating CKD mice with IL-9-neutralizing IgG reduced vein graft neointimal area four-fold, increased vein graft re-endothelialization ~two-fold, and reduced vein graft total and activated mast cell levels two- and four-fold, respectively. Treating CKD mice with the mast cell stabilizer cromolyn reduced neointimal hyperplasia and increased re-endothelialization in vein grafts. In vitro, IL-9 promoted endothelial cell apoptosis but had no effect on smooth muscle cell proliferation. Conclusion CKD aggravates vein graft disease through mechanisms involving IL-9 and mast cell activation.

KW - Cytokines

KW - Endothelial cells

KW - Mast cells

KW - Neointimal hyperplasia

KW - Smooth muscle cells

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